The purpose of this study is to assess the safety, efficacy and pharmacokinetics of GreenGene™ F in subjects with severe hemophilia A previously treated (> 150 exposure days) with a Factor VIII concentrate and without presence or history of inhibitors to FVIII (Factor VIII).

A cohort of 13-18 subjects will be included in the pharmacokinetic (PK) evaluation of GreenGene™ F and an approved recombinant Factor VIII product (Refacto AF); a minimum of 13 of these subjects will be re-evaluated at study end (50 exposure day).

Hemostatic efficacy of GreenGene™ F will be assessed by its effectiveness in controlling spontaneous or traumatic bleeding episodes and by the rate of breakthrough bleeding during prophylaxis over ≥ 50 exposure days.

Hemostatic efficacy of GreenGene™ F will be assessed by its effectiveness in controlling spontaneous or traumatic bleeding episodes and by the rate of breakthrough bleeding in a minimum of 10 on demand treated subjects during 50 exposure days.

Peri-operative hemostatic control of GreenGene™ F in surgery or invasive procedures will be assessed in at least 10 surgeries, some of them major, in at least five subjects

Biological: GreenGene™ F

intra venous infusion,

Surgical substudy:

Minor surgery including tooth extraction = Post in fusion FVIII level of 60-100% of normal. A single bolus infusion (30-50 IU/kg) beginning within one hour of the operation. Optional additional dosing every 12 to 24 hours as needed to control bleeding.

Negative assays for FVIII inhibitor in subject files (<0.6BU Nijmegen assay) No history of positive inhibitor is allowed

Normal liver and kidney function.

Platelet count ≥ 100,000 μL

Normal prothrombin time or International Normalized Ratio (INR) < 1.5

Subjects receiving therapy for human immunodeficiency virus (HIV) or hepatitis must be on a stable treatment regimen

Subjects must be able to withhold FVIII infusions for approximately 72 h prior to each FVIII activity and inhibitor assay (96 h if participating in the PK sub study)

Absolute CD4 lymphocyte cell count ≥ 200 μL

Signed the written informed consent form or informed consent was obtained from the subject's legal guardian

Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [ß hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug

All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e. bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least one month before dosing)

Willing and able to comply with all aspects of the protocol

Exclusion Criteria:

Presence at Screening of FVIII inhibitor ≥ 0.6 BU as tested with the Nijmegen modification of the Bethesda assay in either central or local laboratory

History of FVIII inhibitor of ≥ 0.6 BU as measured using the Nijmegen modification of the Bethesda assay

History of FVIII inhibitor ≥ 1.0 BU if the subject has been tested routinely using the original Bethesda assay, or history of periods with low recovery and no response to Factor VIII treatment

Demonstrated an inability to respond to conventional doses of FVIII therapy

History of incremental recovery of Factor VIII <1.35% per IU/kg infused

Laboratory or clinical evidence of portal vein hypertension including,(but not limited to, an INR > 1.4, the presence of splenomegaly and/or spider angiomata on physical examination and/or a history of esophageal hemorrhage or documented esophageal varices

Uncontrolled hypertension (diastolic blood pressure >100 mm Hg)

Hemoglobin < 10 g.dL

HIV disease symptoms regardless of presence of HIV antibodies

Routine administration (or planned routine administration during the course of the study), of immunosuppressive or immunomodulating drugs other than antiretroviral therapy (e.g., steroids, beta-interferon)

History of hypersensitivity or serious adverse reaction to recombinant or plasma-derived FVIII concentrate

History of pretreatment prior to the administration of FVIII products (e.g., of antihistamines)

Regular use of antifibrinolytics or medications affecting platelet function

Hypersensitivity to hamster-or mouse derived proteins

Blood transfusions within 30 days of enrollment into the study

Current participation in another investigational drug or device study, or participated in a clinical study involving an investigational drug or device within 30 days of enrollment into the study

Unable or unwilling to cooperate with study procedures

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01619046